Abstract

Alzheimer's disease (AD) can be identified prior to the occurrence of dementia by
using biomarkers. Three phases of AD are recognized: an asymptomatic biomarker-positive
phase, a phase with positive biomarkers and mild cognitive deficits, and a dementia
phase. Codification of these phases was first accomplished in 2007 by an International
Work Group (IWG) led by Bruno Dubois. The definitions relevant to the approach were
further clarified in 2010. In 2011, the National Institute on Aging/Alzheimer's Association
(NIA/AA) established three work groups to develop definitions and criteria for these
three phases of AD. The criteria of the IWG and those of the NIA/AA have many similarities
and important differences. The two sets of criteria concur in recognizing the onset
of AD prior to dementia. The three phases of AD described in both sets of criteria
embrace the same clinical entities but with different terminologies and emphases.
IWG criteria emphasize a single clinico-biological approach that includes all symptomatic
phases of AD and uses the same diagnostic framework across the spectrum of symptomatic
disease; the NIA/AA criteria apply different diagnostic approaches to the three phases.
Biomarkers are an integrated and required part of the IWG criteria and are optional
in the NIA/AA approach. Both sets of criteria have substantial strengths, but new
information demonstrates shortcomings that can be addressed in future revisions of
the criteria. These new criteria have profound implications, including greatly increasing
the number of people identified as suffering from AD and increasing the time that
patients will spend with knowledge of the presence of the disease.

Review

Alzheimer's disease (AD) has traditionally been defined as a type of dementia, and
criteria have been provided by the National Institute of Neurological and Communicative
Disorders and Stroke - Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA)
[1], the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) [2], and the 10th revision of the International Classification of Diseases (ICD-10) [3]. Of these sets of criteria, the NINCDS-ADRDA criteria were most widely used in dementia
research. There were several notable aspects of these criteria: (a) patients had to
have cognitive deficits and functional compromise severe enough to meet criteria for
dementia, (b) a confirmed diagnosis depended on postmortem examination, (c) the most
accurate diagnosis that the clinician could make for the living patient was 'probable
AD', (d) other possible causes of cognitive impairment had to be excluded by the clinician,
and (e) the cognitive deficits were not operationalized for characteristics or severity.
When applied by expert clinicians, these criteria have an 80% positive predictive
value and a 60% negative predictive value for the accurate clinical diagnosis of AD
when compared with postmortem examination [4].

Biomarker studies have forced a reconsideration of the time course of AD. Numerous
studies of cerebrospinal fluid (CSF) demonstrate that amyloid beta protein (Aβ) declines
and that total tau and phosphorylated tau levels increase several years before the
onset of AD dementia [5,6]. Similarly, amyloid imaging studies demonstrate that amyloid is deposited in the
brain several years prior to the onset of dementia in AD [6,7]. Atrophy on magnetic resonance imaging (MRI), hypometabolism on fluorodeoxyglucose
(FDG) positron emission tomography (PET), and hypoperfusion on single-photon emission
computed tomography (SPECT) all show abnormalities prior to the onset of dementia
and coincident with or in anticipation of the onset of cognitive impairment [8-10]. These observations indicate that the presence of the pathological process characteristic
of AD can be identified several years before the onset of AD dementia and that the
dementia form of AD represents a late phase of the biological process. On the basis
of data from biomarkers, AD can be reconceptualized as a progressive disorder that
advances from biological changes in the brain with no accompanying cognitive abnormalities,
to a state of memory impairment with biomarker abnormalities indicative of AD, to
mild, moderate, severe, and profound stages of AD dementia.

International Work Group criteria

Dubois and colleagues, of the International Work Group (IWG), developed new criteria
for the diagnosis of AD as a clinico-biological entity [11] and produced a lexicon of terminology to address the complex issues associated with
this marked revision of the way AD is conceived [12]. The author of this review is a member of the IWG. The new criteria have several
important aspects: (a) the diagnosis of AD can be made in the living individual and
is no longer dependent on autopsy confirmation; this is a shift from the clinico-pathological
paradigm to a clinic-biological paradigm; (b) the diagnosis of AD can be made with
greater certainty and does not use the terminology of 'probable AD'; (c) other diseases
can be excluded with biomarkers, addressing the poor negative predictive value of
earlier criteria; (d) the diagnosis of AD can be made prior to the onset of dementia;
(e) the identification of AD pathology placing the person at risk for progressing
to symptomatic AD can be made in asymptomatic individuals; (f) the same clinico-biological
approach and same criteria can be used for diagnosis of all stages of symptomatic
AD regardless of whether dementia is present; (g) the most common phenotype and typical
presentation of AD are a hippocampal type of memory abnormality with poor storage
and more response to cuing as demonstrated on a Free and Cued Selective Reminding
Test; (h) several biomarkers can support the presence of AD pathology and fulfill
the criteria; and (i) pathophysiologic (amyloid imaging and CSF Aβ and tau measures)
and topographic (MRI, FDG PET, and SPECT) biomarkers are recognized [11,12]. In the IWG criteria, the concept of mild cognitive impairment (MCI) is abandoned
in favor of the more specific prodromal AD for those patients with symptomatic predementia
AD. The IWG criteria do not offer any nomenclature for the general nonspecific syndrome
of 'MCI' in favor of developing criteria that use biomarkers to identify that subset
of MCI patients who are in the predementia phase of AD.

Patients without cognitive abnormalities and with positive biomarkers are identified
as having AD pathology, an AD risk state. The IWG describes AD as a clinic-biological
disorder; if no symptoms are present, then this is not a disease state. The presence
of the biomarker represents a risk factor for progressing to AD in the future. The
proportion of people who progress, the time frame for progression, and additional
risk factors for progression are currently not fully defined [13-15]. The update of the criteria expanded the identification of different manifestations
of AD dementia or atypical forms of AD dementia, including posterior cortical atrophy,
the frontal variant of AD dementia, and the logopenic presentation of AD dementia
[12].

Although these criteria represent a conceptual advance, they can be improved. Since
the publication of these criteria, it has become evident that the physiological markers
are more specific to the AD bio logical process; topographic markers are more sensitive
to disease progression but less specific to AD [13]. Atrophy, hypometabolism, and hypoperfusion occur in a variety of disease states,
whereas amyloid abnormalities are present in a very restricted number of disorders,
predominantly AD. Moreover, the absence of Aβ abnormalities is strong evidence against
AD as the cause of the cognitive changes, whereas negative findings on MRI, FDG PET,
or SPECT do not have the same negative predictive value.

Requiring a pathophysiologic biomarker to support the presence of AD will improve
diagnostic accuracy. In addition, the IWG criteria recognize atypical forms of AD
dementia but not atypical manifestations of prodromal AD. Extending this diagnostic
framework backwards into prodromal AD will improve diagnostic continuity and sensitivity.
The issue of mutation carriers can also be clarified in the criteria. The presence
of a hippocampal type of amnestic disorder in a patient who has a known causative
mutation and who presents at an age compatible with the mutation expression can be
diagnosed as prodromal AD or AD dementia depending on the presence of the accompanying
functional deficits. Merely being in a family known to carry the mutation, however,
should not be sufficient to make this diagnosis, as there are unusual non-AD causes
of hippocampal amnesia and these can occur in non-carriers of mutation-bearing families.
Revisiting and adjusting the criteria in this way would reduce the opportunity for
diagnostic ambiguity in their application.

National Institute on Aging/Alzheimer's Association criteria

After the two publications of the IWG criteria, the National Institute on Aging (NIA)
and the Alzheimer's Association (AA) convened three working groups to develop criteria
for the asymptomatic, minimally symptomatic, and dementia phases of AD [16-18]. These criteria share many features with the IWG criteria, including recognition
of an asymptomatic biomarker-positive phase of AD pathology, identification of a predementia
symptomatic phase of AD, retention of criteria for AD dementia, integration of biomarkers
into some approaches to the diagnostic process, and categorization of biomarkers into
two types: one identifying Aβ abnormalities and one for neurodegeneration.

A notable aspect of the NIA/AA criteria for the pre-clinical asymptomatic phase of
AD is the description of a sequential appearance of abnormalities from stage 1 with
abnormalities of amyloid only, to stage 2 with bio markers of both amyloid abnormalities
and neurodegeneration, to stage 3 with both types of biomarkers and minimal clinical
decline not meeting criteria for MCI [16].

The predementia symptomatic phase of AD retains the concept of MCI in the NIA/AA approach
[17]. This has the advantage of being able to be implemented in clinical practice where
biomarkers are unavailable. Non-AD as well as AD types of MCI are recognized in the
criteria. There is some ambiguity in the use of 'MCI' versus 'MCI due to AD' in the
criteria. MCI is defined by using the original criteria of Petersen and colleagues
[19]. Biomarkers are not required for the diagnosis of MCI, although the diagnosis of
MCI due to AD would require biomarker support given the heterogeneous nature of the
MCI syndrome [20,21]. For research application, biomarkers are introduced and stratified. If biomarkers
of both amyloid abnormalities and neurodegeneration are present, the term 'MCI due
to AD - high likelihood' is applied; if only one type of biomarker is collected and
is positive, then the term 'MCI due to AD - intermediate likelihood' is used. If no
biomarker is collected, the results are ambiguous, or two biomarkers are contradictory,
then the bio markers are uninformative and the relationship to AD is uncertain. The
NIA/AA MCI approach does not establish a continuity with the criteria suggested for
preclinical AD in which both types of biomarkers are implied to be positive by the
time the patient becomes symptomatic [16].

The stratification of biomarkers offered in the NIA/AA approach is challenging to
apply in practice since biomarkers are not strictly and consistently related to each
other. Patients with MCI and positive amyloid imaging but with an MRI that does not
reach a predefined cutoff for excessive atrophy would receive a diagnosis of MCI due
to AD of uncertain likelihood since the biomarkers are inconsistent with each other,
although there are few competing diagnoses for this set of observations. Likewise,
a patient with MCI and hippocampal atrophy on MRI and negative amyloid imaging would
receive the same diagnosis of MCI due to AD of uncertain likelihood, although the
diagnosis of AD in this case would be biologically unlikely.

MCI is distinguished from dementia by the presence of abnormalities of activities
of daily living (ADLs). This is an arbitrary distinction based on clinical judgment
and is subject to both clinician biases and patient or caregiver reporting errors.
Studies of ADL rating scales in MCI demonstrate that impairment of at least some high-level
instrumental ADLs is common in MCI [22]. Morris [23] analyzed the effect of the NIA/AA criteria on diagnostic divisions. The author showed
that, if these criteria were applied, many conditions currently classified as mild
AD would be identified as MCI. This shift would have many ramifications, including
allowing patients with a more advanced pathology into MCI trials.

The NIA/AA criteria for AD dementia retain most of the features of the past diagnosis
of probable AD [1] despite the limited positive predictive value and poor negative predictive value
of these criteria [4]. Diagnostic standards for all-cause dementia are provided, and 10 categories of dementia
of the AD type - including probable AD dementia, possible AD dementia, probable or
possible AD dementia with evidence of the AD pathophysiological process, and pathophysiologically
proved AD dementia - are established [18]. Probable AD dementia meets clinical diagnostic criteria without supporting biomarker
evidence of AD. Biomarkers are integrated into the criteria to describe probable or
possible AD dementia with pathophysiological evidence of AD and are stratified as
of high likelihood of being due to AD if amyloid abnormalities and evidence of neurodegeneration
are both present and of intermediate likelihood of being due to AD if only one type
of biomarker evidence is present.

The terminology of 'probable AD dementia of intermediate likelihood of being due to
AD' may be confusing for clinical and research application. When NIA/AA criteria are
used, the patient with the clinical syndrome of probable AD, no available structural
imaging, and positive amyloid imaging would be receive a diagnosis of probable AD
of intermediate likelihood of being due to AD, although there are few (if any) alternatives
to the diagnosis of AD in this case. A patient with an AD-like phenotype, atrophy
on MRI, and negative amyloid imaging would receive a diagnosis of probable AD with
uncertain likelihood of AD, although this person is unlikely to have AD. The person
with the AD dementia phenotype and no biomarkers would receive a diagnosis of probable
AD.

The NIA/AA criteria are an improvement over the preceding diagnostic approach of the
NINCDS/ADRDA criteria and are a step toward electively integrating new biomarker information
into a diagnostic framework. Like the IWG criteria, the NIA/AA criteria can be improved.
The use of three different approaches to diagnose the three phases of the same illness
fails to capture the evolving idea of a single disorder occurring along a spectrum
of severity. The concept of a single stereotyped sequence of biomarker and clinical
progression in the preclinical phase of AD does not reflect the heterogeneity of findings
observed in clinical practice [24]. The ambiguity of MCI versus MCI due to AD can be clarified, and the diagnostic complexity
of the approach to AD dementia offered can be simplified to assist in clinical application.
The criteria for identifying someone as manifesting MCI rather than mild AD may not
be sufficiently stringent [23]. The stratification of biomarkers used in both the MCI and AD dementia approaches
is challenging in clinical implementation; the data support the diagnostic specificity
of amyloid biomarkers over biomarkers of neurodegeneration and these observations
can be incorporated into improved criteria.

Implications of new criteria

Two pivotal reconceptualizations of AD have occurred in the history of our understanding
of this disease, and both have led to dramatic increases in the recognition of the
number of people affected. The first was led by Robert Katzman, who in 1976 [25] drew attention to the identity between 'presenile' AD and 'senile dementia'. He recognized
that AD is the major cause of progressive cognitive impairment in the elderly and
is bound to grow to epidemic proportions with the aging of the world's population.
The second is the pioneering work of the IWG. This work synthesizes the available
evidence into a cohesive framework for recognition of AD as a clinic-biological disorder
that can be diagnosed in life and embraces a spectrum of severity from very mild symptoms
to profound dementia [11,12]. This change in paradigm also has the effect of greatly increasing the number of
individuals recognized as manifesting AD. The projection of 80 million cases of AD
by 2040 [26] is based on projections of AD dementia and will be multiplied by a factor of at least
2 if predementia cases of AD are included.

Another effect of making the diagnosis earlier in the disease and including predementia
cases in the diagnosis of AD is the dilemma it raises for patient care [27]. Patients deserve to know what the clinician knows and to be informed about the limits
of our knowledge. The diagnosis of prodromal AD is often - but not always - associated
with transition to AD dementia over the ensuing few years. Hertze and colleagues [28] found that 71% of patients with the syndrome of MCI and AD-type CSF findings, including
low Aβ and high tau, progressed to AD dementia within 5 years. Twenty-nine percent
of such patients did not develop a dementia syndrome and were cognitively stable even
after half a decade of observation [28]. This represents uncertainty for the physician and hope for the patient and patient's
family. When individuals are given a diagnosis of prodromal AD, they will carry the
diagnosis of AD for many years and must be resigned to the uncertainty of the duration
of this phase of the disorder. Helping patients live with AD will be a major theme
of coming research and care.

Comment

Rapidly evolving information about the biology of AD and biomarker windows on the
disorder are reshaping our understanding of the disease at an accelerating pace. The
IWG and the NIA/AA work groups support the diagnosis of AD prior to the onset of dementia
and point to how best to integrate biomarkers into diagnostic criteria. Both sets
of available criteria can be revised to better capture current data on the role of
amyloid as a diagnostic hallmark and early indicator of the presence of the AD.

An important goal of developing new criteria is to support clinical trials and advance
the new therapeutics for AD. So that optimal cognitive function is maintained and
the progression of AD into the dementia phase is deferred, a diagnostic framework
for predementia AD is needed. Many trials have involved patients with diagnosed MCI
and none has led to the development of a new treatment or extension of currently available
treatments into the MCI phase of AD. The heterogeneity of MCI and the lack of uniform
biological targets in this non specific syndrome may have contributed to these failures
[20,21]. IWG criteria for prodromal AD have been successfully implemented in current phase
2 clinical trials for small molecules, immunotherapies, and medical foods and have
been accepted by the European Medicines Agency [29,30] for use in AD clinical trials. A conundrum in the clinical trial application of research
diagnostic criteria is how to make them specific enough to capture a population with
a homogeneous biology but not so narrow that they exclude many patients who have AD
but who lack a specific phenotype or biomarker profile.

The preclinical phase of AD (NIA/AA criteria) or AD risk state (IWG criteria) sets
the stage for the implementation of prevention trials of individuals who do not have
symptoms of AD but who harbor the amyloid changes that have been associated with the
presence of the disease. The goal of these studies will be to delay the onset of cognitive
and functional decline. Such studies will be facilitated by refined diagnostic criteria.

The emergence of biomarkers is the basis for both justifying and formulating new diagnostic
criteria. Without progress in biomarkers, there would be no need for new criteria.
The IWG criteria require both clinical and biomarker evidence to identify the different
phases of AD and AD pathology. In NIA/AA criteria, use of biomarkers is optional and
clinical information alone can suffice for diagnosis of MCI or probable AD dementia.
Among biomarkers, amyloid abnormalities may have a particularly informative role in
AD risk states and prodromal AD.

Regulatory language used with the recent approval of florbetapir emphasizes that negative
amyloid imaging in persons with cognitive impairment is inconsistent with identifying
neuritic plaques as the cause of the cognitive decline and therefore inconsistent
with a diagnosis of AD as the cause of the cognitive syndrome. AD is not currently
excluded with negative amyloid imaging in either set of diagnostic criteria. It will
be important to align regulatory and clinical criteria in future versions of these
diagnostic approaches.

Positive amyloid imaging is less informative than negative imaging and occurs in patients
with AD, Lewy body dementia of the AD type, or amyloid angiopathy and in cognitively
normal persons [31,32]. The combination of careful description of the phenotype in conjunction with the
use of biomarkers is critical to accurate diagnosis and will be assisted by diagnostic
criteria.

Both sets of criteria emphasize the research nature and need for studies of the sensitivity,
specificity, and positive and negative predictive value of the criteria. The urgent
need of clinicians for guidance in how to apply biomarkers and improve diagnostic
standards means that new technologies and approaches will be incorporated rapidly
into clinical practice where the appropriate biomarkers are available. Rapidly advancing
research on biomarkers provides new information with which to revise the criteria
and enhance their clinical utility. This is a necessary step toward advancing new
and desperately needed treatments for AD.